Correlations between lymph node metastasis and depth of submucosal invasion in submucosal invasive colorectal carcinoma: a Japanese collaborative study

Background Depth of submucosal invasion (SM depth) in submucosal invasive colorectal carcinoma (SICC) is considered an important predictive factor for lymph node metastasis. However, no nationwide reports have clarified the relationship between SM depth and rate of lymph node metastasis. Our aim was to investigate the correlations between lymph node metastasis and SM depth in SICC.Methods SM depth was measured for 865 SICCs that were surgically resected at six institutions throughout Japan. For pedunculated SICC, the level 2 line according to Haggitts classification was used as baseline and the SM depth was measured from this baseline to the deepest portion in the submucosa. When the deepest portion of invasion was limited to above the baseline, the case was defined as a head invasion. For nonpedunculated SICC, when the muscularis mucosae could be identified, the muscularis mucosae was used as baseline and the vertical distance from this line to the deepest portion of invasion represented SM depth. When the muscularis mucosae could not be identified due to carcinomatous invasion, the superficial aspect of the SICC was used as baseline, and the vertical distance from this line to the deepest portion was determined.Results For pedunculated SICC, rate of lymph node metastasis was 0% in head invasion cases and stalk invasion cases with SM depth <3000µm if lymphatic invasion was negative. For nonpedunculated SICC, rate of lymph node metastasis was also 0% if SM depth was <1000µm.Conclusions These results clarified rates of lymph node metastasis in SICC according to SM depth, and may contribute to defining therapeutic strategies for SICC.     

New indication for endoscopic treatment of colorectal carcinoma with submucosal invasion

BACKGROUND AND AIMS: Although an increasing number of early colorectal cancers (CRC) have been curatively treated by endoscopy, there have been no definitive criteria to decide the effectiveness of such therapy. We retrospectively analyzed clinicopathological factors to establish criteria for curative endoscopic treatment of early CRC. METHODS: First, risk factors of lymph node metastasis were analyzed in 171 patients who received surgery with postoperative histology of CRC submucosal invasion. The resultant new criteria were evaluated in another 60 patients who experienced endoscopic resection of CRC and surgery according to the current criteria most often used in Japan. RESULTS: In the first substudy, lymph node metastasis was present in 18 of 171 patients (10.5%). Lymphatic permeation, sprouting and infiltrative growth of cancer cells were identified as histological factors significantly related to lymph node metastasis, and observed in much higher rates when the depth of submucosal invasion was beyond 1,500 micron. The minimum depth with positive lymph nodes was 1,075 micron. In the second group of 60 patients, lymph node metastasis was recorded in none of nine patients who met our new criteria of complete endoscopic treatment: submucosal invasion below 1,500 micron in depth, and no lymphatic permeation, sprouting or infiltrative growth pattern on tumor histology. Lymph node metastasis was positive in three of the other cases who did not meet our new criteria. CONCLUSIONS: The present study showed that endoscopic treatment of early CRC may be considered complete when submucosal invasion beyond 1,500 micron, lymphatic permeation, sprouting, and infiltrating growth are all denied.     

Expression of adhesion molecules in hepatic metastases of colorectal carcinoma: Relationship to primary tumours and prognosis after hepatic resection

BACKGROUND: Adhesion molecules are closely involved in the development and growth of metastatic tumours. METHODS: We examined the expression of two adhesion molecules in liver metastatic tumours originating from colorectal carcinomas and correlated the expression of E-cadherin (EC) and CD44 variant exon 6 (v6) in these tumours with prognosis after hepatic resection. We examined 39 primary colorectal and 44 liver metastatic tumours obtained from 39 patients and 30 non-metastatic colorectal carcinomas as controls. The expression of EC in primary colorectal carcinomas of the metastasis group was significantly lower than in the non-metastasis group (P < 0.05). The expression of EC was low in metastatic liver tumours. RESULTS: The expression of CD44v6 in primary colorectal carcinomas of the metastasis group was significantly higher than in the non-metastasis group (P < 0.01). Expression of CD44v6 was high in metastatic liver tumours. However, there was no correlation between the expression of EC and CD44v6 or between each of these molecules and clinicopathological features of primary and metastatic tumours. Negative expression of EC and CD44v6 was a poor prognostic factor for survival after hepatic resection. CONCLUSIONS: Our results indicate that the lack of expression of EC and CD44v6 in liver metastases of colorectal cancer is associated with poor survival after surgery.     

Actual number of tumor budding as a new tool for the individualization of treatment of T1 colorectal carcinomas

BACKGROUND AND AIM: Treatment of T1 colorectal carcinomas, either local excision including endoscopic polypectomy or radical surgery, has always been problematic in everyday practice. Although previous studies have revealed that tumor budding at the invasive margin can be a marker for the malignant potential of T1 colorectal carcinomas, the evaluation of tumor budding has not been standardized as yet. In the present study, we attempted to apply the actual number of tumor budding units for the individualization of treatment in T1 colorectal carcinomas. METHODS: In 76 T1 colorectal carcinomas, associations between lymph node metastasis and clinicopathological parameters were examined statistically. A mathematical formula for predicting the risk of lymph node metastasis was constructed and decision analysis was attempted to determine individually the indication for additional surgery after endoscopic mucosal resection of T1 colorectal carcinomas. RESULTS: Of the clinicopathological parameters examined, multivariate analysis showed that the actual number of tumor budding units alone was significantly associated with lymph node metastasis. The probability of lymph node metastasis was calculated as Z = 0.07 x (budding counts) - 3.726, probability = 1/1 + e(-Z). The more the budding counts, the higher the probability of lymph node metastasis. This formula was able to accurately predict lymph node metastasis in successive cases. The actual number of tumor budding units can be applied to decision analysis in determining an indication for additional surgery after endoscopic mucosal resection of T1 colorectal carcinomas. CONCLUSIONS: The actual number of tumor budding units may be useful in the decision making for patient-oriented treatment of T1 colorectal carcinomas.     

Clinical significance of serum levels of CD44 variant exons 8–10 protein in colorectal cancer

We examined serum levels of a CD44 splice variant that contained variant exons 8–10 (CD44v8–10) as a tumor marker in colorectal cancer patients. We performed enzyme-linked immunosorbent assays in 81 sera obtained from 71 colorectal cancer patients and 10 healthy controls. Serum CD44v8–10 levels were significantly higher in the colorectal cancer patients than in the healthy controls (0.209 ± 0.098 versus 0.114 ± 0.019 OD; P < 0.01). There was a close correlation between immunohistochemical expression and serum CD44v8–10 levels. Surgical resection of the tumors resulted in a reduction of serum CD44v8–10 levels. There was no significant correlation between serum CD44v8–10 level and serosal invasion or histologic type. However, a significant correlation was observed between serum CD44v8–10 level and lymphatic or venous invasion. In addition, serum CD44v8–10 levels were significantly higher in carcinomas associated with lymph node or liver metastasis than in those without metastasis. These findings suggest the usefulness of serum CD44v8–10 level in the prediction of colorectal cancer metastasis. (Received July 25, 1997; accepted Nov. 28, 1997)     

Analysis of lymphatic and blood vessel invasion biomarkers in T1 esophagogastric adenocarcinomas for improved patient prognostication

Lymphovascular invasion (LVI) in T1 esophagogastric adenocarcinoma may predict risk of recurrence despite definitive treatment with surgery or endoscopic resection. Podoplanin and CD34 are emerging biomarkers of lymphatic and blood vessel invasion, respectively, and could be adopted to refine LVI assessment. A consecutive series of 65 patients with T1 adenocarcinomas diagnosed at Nottingham University Hospitals were investigated. T1 tumors from 43/65 patients who received primary surgery only were suitable for LVI evaluation by hematoxylin and eosin (H&E) staining as well as by CD34 and Podoplanin immunohistochemistry. LVI was correlated to clinicopathological features and recurrence free survival. H&E staining detected LVI in 11.6% (5/43) of T1 tumors. CD34 and Podoplanin immunohistochemistry significantly improved LVI detection to 25.6% (11/43). Compared with LVI by H&E, immunohistochemical evaluation of blood vessel invasion (CD34) or lymphatic vessel invasion (Podoplanin) was significantly associated with higher grade (P = 0.005), submucosal invasion (T1b) (P = 0.018), lymph node positivity (N1) (P = 0.029) and poor recurrence free survival (P = 0.0003). Our study provides evidence that CD34 and Podoplanin immunohistochemistry could improve LVI detection and allow better prognostication of patients and optimum selection of definitive treatment. Larger multicenter studies are required for further validation that could have significant clinical implications.     

Impact of endoscopic submucosal dissection for the therapeutic strategy of large colorectal tumors

Background and Aims: The change of therapeutic strategy for large colorectal tumors after the introduction of endoscopic submucosal dissection (ESD) has not yet been clarified. The aim of this study was to estimate the impact of ESD as an initial treatment strategy. Methods: A questionnaire was administered to nine expert panelists in colorectal ESD. The questionnaire used retrospective data from consecutive case series. Forty‐seven cases of early colorectal tumors (≥ 20 mm) were included. Endoscopic growth types were 25 laterally‐spreading tumors (LST) of granular type (G), 15 LST of non‐granular types (NG), and seven protruded types. Pathological diagnoses included 15 adenomas (Ad), 18 intramucosal cancers (M), three submucosally‐shallow invasive cancers (< 1000 µm) (SMs), and 11 submucosally‐deep invasive cancers (≥ 1000 µm) (SMd). The expert panelists completed questionnaires about recommended initial treatment under suppositions of before and after the introduction of ESD. Over‐surgery was defined as surgery for Ad, M, and SMs. Non‐curative endoscopic resection (ER) was defined as ER for SMd. Results: After the introduction of ESD, the reduction in the over‐surgery rate was estimated at 10.8% for Ad, M, and SMs, and the increase in the non‐curative ER rate was estimated at 27.2% for SMd. By endoscopic growth type, the reduction of over‐surgery rates for LST–NG, LST–G, and protruded type was 15.5%, 10.5%, and 2.2%, respectively. Conclusions: The endoscopists changed their therapeutic strategy for large colorectal tumors to reduce over‐surgery, especially in LST–NG, demonstrating the impact of ESD.     

Risk of Lymph Node Metastasis in T1 Carcinoma of the Colon and Rectum

PURPOSE: Several recent reports of high local recurrence and lymph node metastasis in T1 carcinoma of the rectum prompted us to study the risk factors for lymph node metastasis in these lesions. METHODS: We reviewed the clinical records of 7,543 patients who underwent operative treatment for carcinoma of the colon and rectum from 1979 to 1995. Only patients with sessile T1 lesions who underwent colorectal resection were included in the study, yielding an analysis cohort of 353 patients. The following carcinoma-related variables were assessed: size, mucinous subtype, carcinomatous component, grade, site in colon and rectum, lymphovascular invasion, and depth of submucosal invasion. For the depth, the submucosa was divided into upper third (sm1), middle third (sm2), and lower third (sm3). Chi-squared tests and logistic regression were used to evaluate the variables as potential risk factors for lymph node metastasis. RESULTS: The incidence of T1 lesions was 8.6 percent. In the analysis cohort, the lymph node metastasis rate was 13 percent. Significant predictors of lymph node metastasis both univariately and multivariately were sm3 (P = 0.001), lymphovascular invasion (P = 0.005), and lesions in the lower third of the rectum (P = 0.007). Poorly differentiated carcinoma was significant univariately (P = 0.001) but not in the multivariate model. No other parameter was associated with a significant risk. CONCLUSIONS: T1 colorectal carcinomas with lymphovascular invasion, sm3 depth of invasion, and location in the lower third of the rectum have a high risk of lymph node metastasis. These lesions should have an oncologic resection. In a case of the lesion in the lower third of the rectum, local excision plus adjuvant chemoradiation may be an alternative.     

Clinicopathologic evaluation of the trend toward histologically poor differentiation with submucosal invasion in superficial early colorectal adenocarcinomas

We examined differences in the degree of differentiation in intramucosal and submucosal areas of involvement in early colorectal adenocarcinomas of 131 patients and compared these findings with tumor morphology. In addition, K-ras and p53 protein expression was determined in cases where poorly differentiated adenocarcinoma was detected in the submucosa. We identified 6 patients with both intramucosal differentiated (well-to-moderately differentiated) adenocarcinoma and submucosal poorly differentiated adenocarcinoma (MwSp). The morphological tumor type was superficial in all MwSp cases. The observed MwSp adenocarcinomas had a significantly higher frequency of lymphatic invasion than the more common superficial type of adenocarcinoma. Genetic analysis of these MwSp lesions was carried out using the polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) method to detect the presence of K-ras codon 12 point mutations, and an immunologic staining technique was used to identify the presence of p53 protein overexpression. The K-ras mutation rate was 33.3%, and the p53 overexpression rate was 66.7% for the MwSp adenocarcinomas. Our findings suggest that the rapidly reduced histologic differentiation observed in some of these superficial colorectal adenocarcinomas may play a role in their higher degree of invasiveness. Received: November 17, 1999 / Accepted: July 7, 2000     

Predictive factors for lymph node metastasis in t1 stage colorectal Carcinomas

Purpose Selective endoscopie resection may cure early colorectal cancer (Tl), but the management is controversial. There is concern about the small risk of lymph node metastasis, which will not be treated by endoscopie resection alone. The authors sought predictive markers of lymph node metastasis to assist patient management. METHODS: The authors retrospectively analyzed consecutive cases of Tl stage colorectal cancer resected using endoscopie resection or bowel surgery over the period 1979 to 2000. The risk of lymph node metastasis was analyzed using logistic regression model for the markers selected by univariate analysis: the type of initial treatment, depth of submucosal invasion, lymphatic channel invasion, differentiation of histology, and invasive front histology. RESULTS: Two hundred seventy-eight patients were available for study. Twenty-one had lymph node metastasis. Depth of submucosal invasion (2 2,000 yum) and lymphatic channel invasion significantly predicted risk of lymph node metastasis in multivariate analysis. When these two factors were adopted for the prediction of lymph node metastasis, sensitivity, specificity, positive predictive value, and negative predictive value were 100, 55.6, 15.6, and 100 percent, respectively. CONCLUSIONS: Depth of submucosal invasion and lymphatic channel invasion were accurate predictive factors for lymph node metastasis. These two factors could be used in selecting appropriate cases for surgery after endoscopie resection. Poster presentation at meeting of the American Society of Colon and Rectal Surgeons, San Diego, California, June 2 to 7, 2001.     

Lymphatic vessel invasion detected by monoclonal antibody D2-40 as a predictor of lymph node metastasis in T1 colorectal cancer

Objective  When selecting patients who are at high risk for lymph node metastasis, the detection of lymphatic vessel invasion (LVI) is important. We investigated LVI detected by D2-40 staining as a predictor of lymph node metastasis in T1 colorectal cancer. Materials and methods  Clinicopathological factors including LVI were investigated in 136 patients who underwent colectomy with lymph node dissection for T1 colorectal cancer. We used immunostaining with monoclonal antibody D2-40 to detect LVI. Results  Lymph node metastases were found in 18 patients (13.2%), and LVI were detected in 45 (33%); lymph node metastasis was more frequently observed in LVI-positive groups (13/45 vs 5/91, p < 0.001). Both univariate and multivariate analyses revealed that LVI detected by D2-40 and a poorly differentiated histology at the invasion front were independent risk factors of lymph node metastasis. Conclusion  LVI detected by D2-40 is important for the prediction of lymph node metastasis.     

Management of T1 colorectal carcinoma with special reference to criteria for curative endoscopic resection

Background and Aim: In guidelines 2010 for the treatment of colorectal cancer from the Japanese Society for Cancer of the Colon and Rectum (JSCCR), the criteria for identifying curable T1 colorectal carcinoma after endoscopic resection were well/moderately differentiated or papillary histologic grade, no vascular invasion, submucosal invasion depth less than 1000 µm and budding grade 1 (low grade). We aimed to expand these criteria. Methods: A total of 499 T1 colorectal carcinomas, resected endoscopically or surgically, were analyzed. Relationships between clinicopathologic findings and lymph node metastasis were evaluated. Results: Lymph node metastasis was found in 41 (8.22%) of the 499 cases. The incidence of lymph node metastasis was significantly higher in lesions featuring poorly differentiated/mucinous adenocarcinoma, submucosal invasion ≥ 1800 µm, vascular invasion, and high‐grade tumor budding than in other lesions. Multivariate logistic regression analysis showed all of these variables to be independent risk factors for lymph node metastasis. When cases that met three of the JSCCR 2010 criteria (i.e. all but invasion < 1000 µm) were considered together, the incidence of lymph node metastasis was only 1.2% (3/249, 95% confidence interval: 0.25–3.48%), and there were no cases of lymph node metastasis without submucosal invasion to a depth of ≥ 1800 µm. Conclusions: Even in cases of colorectal carcinoma with deep submucosal invasion, the risk of lymph node metastasis is minimal under certain conditions. Thus, even for such cases, endoscopic incisional biopsy can be suitable if complete en bloc resection is achieved.     

Serum levels of interleukin-1β, luteinizing hormone, and prolactin correlate with the expression of CD45 isoforms on CD4+ peripheral blood T lymphocytes in healthy women

 The expected association between age and the CD45 isoforms expression on CD4+ T-PBL is much more obvious in men than in women. We investigated whether or not circulating factors influence the differentiation of CD4+ T-PBL. Peripheral blood samples were obtained from 56 healthy age-matched subjects (28 men and 28 women, 21–55 years old). Mononuclear leukocytes were analyzed by three-color flow cytometry. The serum concentrations of interleukin-1β (IL-1β), interleukin-6, tumor necrosis factor-α (TNF-α), GM colony-stimulating factor, prolactin (Prl), and luteinizing hormone (LH) were determined by ELISA. The expected age-related decrease of naive (CD45RA+,RO–) cells and increase of memory (CD45RA–,RO+) cells among CD4+ T-PBL were observed in men only (p<0.001 and 0.005). In women, these correlations were not significant. On the other hand, in women only, elevated IL-1β was associated with fewer naive and more memory cells among CD4+ T-PBL (p<0.001). In both sexes, IL-1β correlated with the expression of CD25 on CD4+ T-PBL (on either naive or memory cells, p<0.001). Other cytokines or the CD8+ T-PBL showed no significant correlation. In women, the elevation of LH at mid-cycle inversely correlated with the proportion of naive CD4+ T-PBL (p<0.01). Elevated LH was associated with more CD25 on memory CD4+ T-PBL (p<0.01). A significant correlation exists between IL-1β and LH (p<0.001). Furthermore, in both sexes, Prl correlated with the proportion of CD4+ cells among T-PBL. In men, elevated Prl was associated with more naive CD4+ T-PBL (p<0.005), while in women, Prl correlated with more transient CD45RA+, RO+ cells among CD4+ T-PBL and increased TNF-α (p<0.05 for both). Thus, circulating IL-1β could be involved in the expression of CD25 on CD4+ T-PBL and favors the generation of memory CD4+ T-PBL. In women, the IL-1β- and/or mid-cycle-dependent processes seem to overwhelm the age-related changes. Elevated Prl might exert a dual influence: it favors the development of naive CD4+ T lymphocytes and possibly acts in, synergy with other cytokines during immune stimulation. Received: 20 June 1997 / Accepted: 1 August 1997     

Gastric and intestinal phenotypic cell marker expressions in gastric differentiated-type carcinomas: association with E-cadherin expression and chromosomal changes

Gastric and intestinal phenotypic cell markers are widely expressed in gastric carcinomas, irrespective of their histological type. In the present study, the relations between the phenotypic marker expression of the tumour, histological findings, expression of cell adhesion molecules, and the chromosomal changes in gastric differentiated-type carcinomas were examined. The phenotypic marker expression of the tumour was determined by the combination of the expression of the human gastric mucin (HGM), MUC6, MUC2 and CD10, and was evaluated in comparison with the expression of cell adhesion molecules, such as E-cadherin and β-catenin, and chromosomal changes by comparative genomic hybridization (CGH) in 34 gastric differentiated-type carcinomas. Tumours were classified into the gastric- (G-), gastric and intestinal mixed- (GI-), intestinal- (I-), or unclassified- (UC-) phenotype according to the immunopositivity of staining for HGM, MUC6, MUC2, and CD10. G-phenotype tumours were significantly associated with a higher incidence of differentiated-type tumours mixed with undifferentiated-type component, compared with GI- and I-phenotype tumours (88.9 vs 33.3%, P=0.0498 and 88.9 vs 42.9%, P=0.0397; respectively). HGM-positive tumours were significantly associated with a higher incidence of tumours with abnormal expression of E-cadherin, compared with HGM-negative tumours (66.7 vs 21.1%, P=0.0135). GI-phenotype tumours were significantly associated with a higher incidence of tumours with abnormal expression of E-cadherin, compared with I-phenotype tumours (77.8 vs 21.4%, P=0.0131). HGM-negative tumours were significantly associated with higher frequencies of the gains of 19q13.2 and 19q13.3, compared with HGM-positive tumours (57.9 vs 20.0%, P=0.0382 and 63.2 vs 13.3%, P=0.0051; respectively). MUC6-positive tumours were significantly associated with higher frequencies of the gains of 20q13.2, compared with MUC6-negative tumours (71.4 vs 30.0%, P=0.0349). MUC2-positive tumours were significantly associated with the gain of 19p13.3, compared with MUC2-negative tumours (41.2 vs 5.9%, P=0.0391). I-phenotype tumours were significantly associated with higher frequencies of gains of 5p15.2 and 13q33-34, compared with G-phenotype tumours (66.7 vs 0%, P=0.0481, each) and also associated with higher frequencies of gain of 7p21, compared with GI-phenotype tumours (66.7 vs 0%, P=0.0481). Our present results show that gastric differentiated-type carcinomas have different characteristics according to the phenotypic marker expression of the tumour in terms of histological findings, E-cadherin expression and pattern of chromosomal changes.     

Expression of two CD44 variant proteins (v3 and v6 ) in human colorectalcarcinoma and its relevance for prognosis

AIM To evaluate the expression of CD44v3 and v6 protein in colorectal carcinoma and its prognosticsignificance.METHODS One hundred and twenty-one cases of formalin-fixed paraffin-embedded colorectal carcinomaspecimens were retrospectively analyzed using EnvisionTM immunohistochemical method with the monoclonalantibody CD44v3 and v6. The median follow-up time was 67.77 months and the prognostic value of theCD44v3 and CD44v6 was assessed using univariate and multivariate survival analysis.RESULTS The positive rates of CD44v3 and v6 protein were 60.3% and 57.9%, respectively. There wassignificant correlation between CD44v3 immunoreactivity and tumor location, lymph node metastasis, distantmetastasis and Duke's stage (P< 0.05, Spearman correlation test). Significant correlation between CD44v6immunoreactivity and patients' gender, lymph node metastasis, distant metastasis, Duke's stage was alsonoticed (P < 0.05, Spearman correlation test). The 5-year survival rates were 81.25% and 60.27% inCD44v3 negative and positive cases, respectively. As CD44v6, the 5-year survival rates were 80.39% and60.00% in CD44v6 negative and positive cases, respectively; these differences between the two groups ofpatients were significant (P<0.05, Log-rank test). In multivariate analysis using the Cox regression model,CD44v3 expression emerges as an independent prognostic indicator.CONCLUSION CD44v3 and v6 might play some important roles in metastasis of colorectal carcinoma, andCD44v3 expression might be a new useful independent prognostic marker of colorectal carcinoma.     

Clinical utility of tumor markers in hepatocellular and pancreatic carcinomas

Because they show high levels in hepatocellular carcinoma, α-fetoprotein and des-γ-carboxyprothrombin are clinically useful tumor markers for differentiating hepatocellular carcinoma from other hepatic diseases. The two are useful complementary markers of hepatocellular carcinoma because they do not correlate with each other. A typical marker of pancreatic cancer is carbohydrate antigen (CA)19-9. Over a period of more than 10 years, many markers resembling CA19-9 have been identified, but none are markedly superior to CA19-9, and the sensitivity of these markers in pancreatic cancer is only 65%–80%. Tumor markers are not useful for the early diagnosis of either hepatocellular carcinoma or pancreatic cancer. They are, however, considered to be useful for monitoring after treatment.     

Relationship between expression of CD44v6 and nm23-H1 and tumor invasion and metastasis in hepatocellular carcinoma

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